Article: Carboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells

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TitleCarboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
AuthorsChen, F2 3
Yang, DS2 3
Petanceska, S1
Yang, A1
Tandon, A2 3
Yu, G2 3
Rozmahel, R3 4
Ghiso, J1
Nishimura, M2 3
Zhang, DM2 3
Kawarai, T2 3
Levesque, G2 3
Mills, J2 3
Levesque, L2 3
Song, YQ2 3
Rogaeva, E2 3
Westaway, D2 3
Mount, H2 3
Gandy, S1
St GeorgeHyslop, P2 3
Fraser, PE2 3
Issue Date2000
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
CitationJournal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M006986200
AbstractAbsence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).
ISSN0021-9258
2011 Impact Factor: 4.773
2011 SCImago Journal Rankings: 0.793
DOIhttp://dx.doi.org/10.1074/jbc.M006986200
ISI Accession Number IDWOS:000165577700051
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorChen, F
dc.contributor.authorYang, DS
dc.contributor.authorPetanceska, S
dc.contributor.authorYang, A
dc.contributor.authorTandon, A
dc.contributor.authorYu, G
dc.contributor.authorRozmahel, R
dc.contributor.authorGhiso, J
dc.contributor.authorNishimura, M
dc.contributor.authorZhang, DM
dc.contributor.authorKawarai, T
dc.contributor.authorLevesque, G
dc.contributor.authorMills, J
dc.contributor.authorLevesque, L
dc.contributor.authorSong, YQ
dc.contributor.authorRogaeva, E
dc.contributor.authorWestaway, D
dc.contributor.authorMount, H
dc.contributor.authorGandy, S
dc.contributor.authorSt GeorgeHyslop, P
dc.contributor.authorFraser, PE
dc.date.accessioned2011-07-14T07:03:00Z
dc.date.available2011-07-14T07:03:00Z
dc.date.issued2000
dc.description.abstractAbsence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationJournal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M006986200
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M006986200
dc.identifier.epage36802
dc.identifier.isiWOS:000165577700051
dc.identifier.issn0021-9258
2011 Impact Factor: 4.773
2011 SCImago Journal Rankings: 0.793
dc.identifier.issue47
dc.identifier.pmid10962005
dc.identifier.scopuseid_2-s2.0-0034711207
dc.identifier.spage36794
dc.identifier.urihttp://hdl.handle.net/10722/134763
dc.identifier.volume275
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
dc.publisher.placeUnited States
dc.relation.ispartofJournal of Biological Chemistry
dc.relation.referencesReferences in Scopus
dc.subject.meshAlzheimer Disease/metabolism
dc.subject.meshAmyloid Precursor Protein Secretases
dc.subject.meshAmyloid beta-Protein Precursor/*metabolism
dc.subject.meshAnimals
dc.subject.meshAspartic Acid Endopeptidases
dc.subject.meshBiological Markers
dc.subject.meshBrain/metabolism/ultrastructure
dc.subject.meshCell Compartmentation
dc.subject.meshElectrophoresis, Polyacrylamide Gel
dc.subject.meshEndopeptidases/metabolism
dc.subject.meshMembrane Proteins/deficiency/*physiology
dc.subject.meshMice
dc.subject.meshMice, Knockout
dc.subject.meshMicroscopy, Electron
dc.subject.meshPeptide Fragments/*metabolism
dc.subject.meshPresenilin-1
dc.titleCarboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
dc.typeArticle
Author Affiliations
  1. New York University School of Medicine
  2. Toronto General Hospital
  3. University of Toronto
  4. Hospital for Sick Children, Toronto